One of the major needs in cancer prevention is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents.
The concept that inflammation and carcinogenesis are related phenomena has been the subject of many studies that have attempted to link these two processes in a mechanistic fashion (Sporn & Roberts (1986) J. Clin. Invest. 78:329-332; Ohshima & Bartsch (1994) Mutat. Res. 305:253-264). The enzymes that mediate the constitutive synthesis of nitric oxide and prostaglandins from arginine and arachidonate, respectively, have relative little significance for either inflammation or carcinogenesis. In contrast, inducible nitric oxide synthase (iNOS) and inducible cycloxygenase (COX-2) both have critical roles in the response of tissues to injury or infectious agents (Moncada, et al. (1991) Pharmacol. Rev. 43:109-142; Nathan & Xie (1994) Cell 78:915-918; Siebert & Masferrer (1994) Receptor 4(1):17-23; Tamir & Tannebaum (1996) Biochim. Biophys. Acta 1288:F31-F36). These inducible enzymes are essential components of the inflammatory process, the ultimate repair of injury, and carcinogenesis. While physiological activity of iNOS and COX-2 may provide a definite benefit to the organism, aberrant or excessive expression of either iNOS or COX-2 has been implicated in the pathogenesis of many disease processes, particularly in chronic degeneration of the central nervous system, carcinogenesis, septic shock, cardiomyopathy, and rheumatoid arthritis.
Triterpenoids, biosynthesized in plants by the cyclization of squalene, are used for medicinal purposes in many Asian countries; and some, like ursolic and oleanolic acids, are known to exhibit anti-inflammatory and anti-carcinogenic activity (Huang, et al. (1994) Cancer Res. 54:701-708; Nishino, et al. (1988) Cancer Res. 48:5210-5215). However, the biological activity of these naturally-occurring molecules is relatively weak, and therefore the synthesis of new analogs to enhance their potency has been undertaken (Honda, et al. (1997) Bioorg. Med. Chem. Lett. 7:1623-1628; Honda, et al. (1998) Bioorg. Med. Chem. Lett. 8(19):2711-2714).
An ongoing effort for the improvement of anti-inflammatory and antiproliferative activity of oleanolic and ursolic acid analogs led to the discovery of 2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid (CDDO) and related compounds (Honda, et al. (1997) supra; Honda, et al. (1998) supra; Honda, et al. (1999) Bioorg. Med. Chem. Lett. 9(24):3429-3434; Honda, et al. (2000) J. Med. Chem. 43:4233-4246; Honda, et al. (2000) J. Med. Chem., 43:1866-1877; Honda, et al. (2002) Bioorg. Med. Chem. Lett. 12:1027-1030; Suh, et al. (1998) Cancer Res. 58:717-723; Suh, et al. (1999) Cancer Res., 59(2):336-341; Suh, et al. (2003) Cancer Res. 63:1371-1376; Place, et al. (2003) Clin. Cancer Res. 9:2798-2806; Liby, et al. (2005) Cancer Res. 65:4789-4798).
Furthermore, U.S. Pat. Nos. 6,326,507, 6,552,075, 7,288,568, 7,863,327, 8,034,955, US 2009/0060873, US 2009/0048204, WO 2008/136838 and WO 2009/023232 teach the use of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and derivatives thereof such as 2-cyano-3,12-dioxoolean-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) and amide derivatives, for the treatment of diseases such as cancer, Alzheimer's disease, Parkinson's disease, inflammatory bowel diseases, and multiple sclerosis. Similarly, U.S. Pat. No. 6,974,801 and WO 2004/064723 teach the use of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile (CNDDO), 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl) imidazole (CDDO-Im), 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl)-2-methylimidazole, and 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl)-4-methylimidazole in the prevention or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, rheumatoid arthritis, and other inflammatory diseases. Furthermore, the use of triterpenoids such as CDDO, CDDO-Me, CDDO-Im, and CDDO-Ethylamide in stimulating the growth and repair of bone and cartilage (US 2008/0233195 and WO 2008/064132) as well as in inhibiting HIV-1 replication (WO 2005/046732) has been described. US 2009/0326063 further teaches the use of synthetic triterpenoids in the prevention and treatment of renal/kidney disease, insulin resistance/diabetes, fatty liver disease, and/or endothelial dysfunction/cardiovascular disease.
Combination therapies of CDDO or CDDO-Me and a chemotherapeutic agent, immunosuppressive agent, or proteasome inhibitor are described in U.S. Pat. No. 7,435,755, U.S. Pat. No. 7,795,305, US 2009/0018146, US 2009/0048205, WO 2002/047611 and WO 2009/023845 for the treatment of cancer and graft versus host disease. Moreover, formulations for improved oral bioavailability of CDDO-Me are disclosed in WO 2010/093944.
Furthermore, CDDO-Me suppresses the induction of several important inflammatory mediators, such as iNOS, COX-2, TNFα, and IFNγ, in activated macrophages. CDDO-Me has also been reported to activate the Keap1/Nrf2/ARE signaling pathway resulting in the production of several anti-inflammatory and antioxidant proteins, such as heme oxygenase-1 (HO-1). These properties have made CDDO-Me a candidate for the treatment of neoplastic and proliferative diseases, such as cancer. Moreover, synthetic triterpenoids have been found to induce apoptosis and differentiation and inhibit proliferation in human leukemia cells (Ikeda, et al. (2003) Cancer Res. 63:5551-5558; Konopleva, et al. (2002) Blood 99(1):326-335; Suh, et al. (1999) supra; Ito, et al. (2000) Mech. Dev. 97:35-45), induce osteoblastic differentiation in osteosarcoma cells (Ito, et al. (2001) Antimicrob. Agents Chemother. 45:1323-1336), enhance neuronal growth factor-induced neuronal differentiation of rat PC12 pheochromocytoma cells, and induce adipogenic differentiation of fibroblasts into adipocytes (Suh, et al. (1999) supra). CDDO-Me has also been found an effective drug for improving kidney function in patients suffering for renal/kidney disease using CDDO-Me (U.S. Pat. No. 8,129,429).
Given the activity of CDDO and CDDO-Me, additional oleanolic acid derivatives have been developed for use in treating cancer, cardiovascular disease, neurodegenerative disease, renal/kidney disease, diabetes, arthritis and inflammatory conditions such as obesity, hypertension, atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, myonecrosis, ulcerative colitis, Crohn's disease, irritable bowel syndrome, retinopathy and metabolic syndrome. See U.S. Pat. NoS. 7,915,402, 7,943,778, US 2010/0048887, US 2010/0048892, US 2010/0048911, US 2011/0245206 and US 2011/0245233.
In view of the therapeutic activities of this class of triterpenoids, it would be advantageous to have compounds with improved activity.